Acne vulgaris is a common condition of the pilo-sebaceous units of the skin (hair follicles and oil glands). Acne is the most common skin disorder in the United States, affecting 40-50 million Americans. Acne usually begins in puberty, but the condition is not restricted to any age group. Approximately 85% of people between the ages of 12 and 24 experience at least minor, most often on the face, chest, and back [Bhate and Williams].
Acne is caused by four major factors: (1) production of oil by enlarged oil glands in the skin, (2) blockage of the hair follicles that release oil, (3) growth of bacteria, called Propionibacterium acnes (P. acnes), within the hair follicles and (4) inflammatory/immune response to P. acnes. 
The pathophysiologic features of acne suggest that combination therapy should be utilized as early as possible to simultaneously attack the multiple pathogenic factors of the condition [Gollnick and Cunliffe]. Antimicrobials have been a mainstay of acne treatment for many years, having multiple mechanisms of action. The most important may be the ability of antibiotics to decrease the number of P. acnes in and around the follicle. They have a bacteriostatic effect on P. acnes, which prevents the bacteria from producing pro-inflammatory molecules [Leyden et al.].
In clinical practice, it is common for physicians to prescribe multiple topical products for acne. Topical products are applied one or two times a day by the patient. However, many of these compounds are irritating with resultant development of facial erythema and discontinuation of the products or noncompliance with therapy. Benzoyl peroxide (BPO) and all trans retinoic acid (ATRA) are two active ingredients with different pharmacological actions that are commonly used for the treatment of acne.
Topical retinoids are keratinization inhibitors. They work by decreasing the cohesiveness of follicular epithelial cells. This, results in an inhibition in the formation of microcomedones, preventing the formation of mature comedones and inflammatory lesions [Gollnick and Cunliffe]. Use of retinoids promotes the normal desquamation of follicular epithelium. The action of the retinoid may enhance the penetration of other topical compounds used to treat acne.
BPO is a commonly used topical antibacterial agent for acne available either by prescription in combinations or over the counter (OTC). BPO has been found to be lethal to P. acnes as well as other bacteria that may reside on the skin. So far there has been no indication of any bacteria developing a resistance to BPO. It has also been demonstrated that BPO has keratolytic activity contributing to its efficacy in treating comedonal acne [Tanghetti]. BPO reduces the cohesiveness of the cells of the stratum corneum, thus improving topical drug delivery through the epidermal barrier.
Silica microcapsule systems have been developed to overcome many of the limitations (such as degradation and irritation) of standard pharmaceutical formulations involving multiple active ingredients. The encapsulation of active ingredients in silica microcapsules serves to protect components in the formulation from interacting with one another and, as a consequence, increases overall formulation stability. Silica is chemically inert, photochemically and physically stable, and safe for topical use.
Applicant's silica encapsulated products meet the criteria for categorical exclusion defined in 21 CFR 25.31(e), and that to the knowledge of Applicant, no extraordinary circumstances exist as defined in 21 CFR 25.21. Thus, no environmental assessment is required according to 21 CFR 25.20(1). For the case of encapsulated BPO (E-BPO)/encapsulated ATRA (E-ATRA), microencapsulation of both BPO and tretinoin protects the tretinoin from oxidative decomposition by BPO, thereby enhancing the stability for this novel combination product and ensuring a suitable clinical and commercial shelf life (U.S. Pat. No. 8,617,580 and US 2012/0202695).
Clinicians have been reluctant to prescribe topical retinoids and BPO concurrently due to a belief that the BPO may result in oxidation and degradation of the tretinoin molecule, thereby reducing its effectiveness, and prefer to recommend the BPO or an antibiotic/BPO combination to be applied in the morning and tretinoin at night (Yan A C. Current concepts in acne management. Adolesc. Med. Clin. 2006; 17(3):613-637.)
Another publication (Emmy Graber, Treatment of Acne Vulgaris, UpToDate.com, July 2016) states “topical tretinoin should NOT be applied at the same time as benzoyl peroxide”, despite the known fact that newer retinoid compositions like Retin A microspheres (MICROSPONGE® System) have less interaction or no short term interaction with BPO. Obviously, concomitant administration of tretinoin and BPO is taught away by this publication.
Unlike adapalene, which is often combined with BPO, tretinoin is significantly more irritant to the skin and since BPO is also irritant, it has been feared that the two APIs together will create unacceptable cutaneous side effects. Also, BPO is known to oxidize tretinoin and hence it was feared that their interaction on the skin when administered together will diminish the therapeutic effect of tretinoin. Thus, while there are some reports in the literature on the value of both compounds being administered one in the morning and the other in the evening, the verdict up to now was that the two products should not be administered concomitantly.
This belief of the medical profession explains why all previous attempts to solve the stability problem of tretinoin/BPO, such as microencapsulation technology, did not yield a commercial product so far.
Combination topical therapy is the recommended standard of care for the management of patients with acne [Gollnick and Cunliffe]. Combination therapy targets multiple pathogenic factors: abnormal follicular keratinization, P. acnes proliferation and inflammation. Combining the separate product applications into a single delivery system would provide the patient with the convenience of a single product, thus improving patient adherence and improving treatment outcomes.